4-1793594-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000142.5(FGFR3):c.-103+129C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.592 in 149,608 control chromosomes in the GnomAD database, including 28,944 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.59 (28710 hom., cov: 30)
  • Exomes 𝑓: 0.72 (234 hom.)
• Consequence: FGFR3 NM_000142.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.95

Genes affected

FGFR3 (HGNC:3690): (fibroblast growth factor receptor 3) This gene encodes a member of the fibroblast growth factor receptor (FGFR) family, with its amino acid sequence being highly conserved between members and among divergent species. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein would consist of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member binds acidic and basic fibroblast growth hormone and plays a role in bone development and maintenance. Mutations in this gene lead to craniosynostosis and multiple types of skeletal dysplasia. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 4-1793594-C-A is Benign according to our data. Variant chr4-1793594-C-A is described in ClinVar as [Benign]. Clinvar id is 680176.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.86 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR3	NM_000142.5	c.-103+129C>A		intron_variant		ENST00000440486.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR3	ENST00000440486.8	c.-103+129C>A		intron_variant		5	NM_000142.5	P4

Frequencies

GnomAD3 genomes AF: 0.591 AC: 87844 AN: 148618 Hom.: 28701 Cov.: 30

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.747

Gnomad AMR AF: 0.654

Gnomad ASJ AF: 0.589

Gnomad EAS AF: 0.882

Gnomad SAS AF: 0.690

Gnomad FIN AF: 0.744

Gnomad MID AF: 0.562

Gnomad NFE AF: 0.709

Gnomad OTH AF: 0.597

GnomAD4 exome AF: 0.722 AC: 637 AN: 882 Hom.: 234 AF XY: 0.723 AC XY: 454 AN XY: 628

Gnomad4 AFR exome AF: 0.333

Gnomad4 AMR exome AF: 0.643

Gnomad4 ASJ exome AF: 0.700

Gnomad4 EAS exome AF: 0.885

Gnomad4 SAS exome AF: 0.647

Gnomad4 FIN exome AF: 0.722

Gnomad4 NFE exome AF: 0.743

Gnomad4 OTH exome AF: 0.472

GnomAD4 genome AF: 0.591 AC: 87868 AN: 148726 Hom.: 28710 Cov.: 30 AF XY: 0.596 AC XY: 43257 AN XY: 72596

Gnomad4 AFR AF: 0.286

Gnomad4 AMR AF: 0.654

Gnomad4 ASJ AF: 0.589

Gnomad4 EAS AF: 0.882

Gnomad4 SAS AF: 0.691

Gnomad4 FIN AF: 0.744

Gnomad4 NFE AF: 0.709

Gnomad4 OTH AF: 0.600

Alfa AF: 0.530 Hom.: 1699

Bravo AF: 0.571

Asia WGS AF: 0.728 AC: 2235 AN: 3072

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	9.1
Dann	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4450996; hg19: chr4-1795321;